Endogenous Kynurenic Acid and Neurotoxicity

Urbańska, Ewa M.; Chmiel-Perzyñska, Iwona; Perzyński, Adam; Derkacz, Marek; Owe‐Larsson, Björn

doi:10.1007/978-1-4614-5836-4_92

Cited by 11 publications

(17 citation statements)

References 204 publications

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“…As a broad-spectrum antagonist of glutamate receptors, displaying high affinity for the glycine site of the N -methyl-d-aspartate complex, KYNA was shown to counteract cytotoxicity in various experimental paradigms. 9 Furthermore, KYNA as an endogenous ligand of the aryl hydrocarbon receptor (AhR) and G-protein-coupled receptor 35 (GPR35), can display anti-inflammatory actions. 8,9 Peripheral KYNA is produced enzymatically, mostly, although not exclusively, in the process of transamination of KYN by aminotransferases (KATs) I–IV.…”

Section: Introductionmentioning

confidence: 99%

“…9 Furthermore, KYNA as an endogenous ligand of the aryl hydrocarbon receptor (AhR) and G-protein-coupled receptor 35 (GPR35), can display anti-inflammatory actions. 8,9 Peripheral KYNA is produced enzymatically, mostly, although not exclusively, in the process of transamination of KYN by aminotransferases (KATs) I–IV. 10,11 In the periphery, synthesis of KYNA occurs in a variety of cells and tissues, including endothelial and epithelial cells, fibroblasts, leukocytes, erythrocytes or myocytes.…”

Section: Introductionmentioning

confidence: 99%

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Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease

Dudzińska

Szymona

Kloc

et al. 2019

Therap Adv Gastroenterol

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Background:Complex interaction of genetic defects with environmental factors seems to play a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Accumulating data implicate a potential role of disturbed tryptophan metabolism in IBD. Kynurenic acid (KYNA), a derivative of tryptophan (TRP) along the kynurenine (KYN) pathway, displays cytoprotective and immunomodulating properties, whereas 3-OH-KYN is a cytotoxic compound, generating free radicals.Methods:The expression of lymphocytic mRNA encoding enzymes synthesizing KYNA (KAT I–III) and serum levels of TRP and its metabolites were evaluated in 55 patients with IBD, during remission or relapse [27 patients with ulcerative colitis (UC) and 28 patients with Crohn’s disease (CD)] and in 50 control individuals.Results:The increased expression of KAT1 and KAT3 mRNA characterized the entire cohorts of patients with UC and CD, as well as relapse–remission subsets. Expression of KAT2 mRNA was enhanced in patients with UC and in patients with CD in remission. In the entire cohorts of UC or CD, TRP levels were lower, whereas KYN, KYNA and 3-OH-KYN were not altered. When analysed in subsets of patients with UC and CD (active phase–remission), KYNA level was significantly lower during remission than relapse, yet not versus control. Functionally, in the whole groups of patients with UC or CD, the TRP/KYN ratio has been lower than control, whereas KYN/KYNA and KYNA/3-OH-KYN ratios were not altered. The ratio KYN/3-OH-KYN increased approximately two-fold among all patients with CD; furthermore, patients with CD with relapse, manifested a significantly higher KYNA/3-OH-KYN ratio than patients in remission.Conclusion:The presented data indicate that IBD is associated with an enhanced expression of genes encoding KYNA biosynthetic enzymes in lymphocytes; however, additional mechanisms appear to influence KYNA levels. Higher metabolic conversion of serum TRP in IBD seems to be followed by the functional shift of KYN pathway towards the arm producing KYNA during exacerbation. We propose that KYNA, possibly via interaction with aryl hydrocarbon receptor or G-protein-coupled orphan receptor 35, may serve as a counter-regulatory mechanism, decreasing cytotoxicity and inflammation in IBD. Further longitudinal studies evaluating the individual dynamics of TRP and KYN pathway in patients with IBD, as well as the nature of precise mechanisms regulating KYNA synthesis, should be helpful in better understanding the processes underlying the observed changes.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease

Dudzińska

Szymona

Kloc

et al. 2019

Therap Adv Gastroenterol

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“…KYNA is a biologically active metabolite of tryptophan, produced from its direct bioprecursor, kynurenine, along one arm of the kynurenine pathway. Second metabolic route of kynurenine generates mostly toxic compounds, such as 3-hydroxykynurenine or quinolinate [14,15]. Noteworthy, KYNA, produced in large quantities by the endothelium [15], seems to be tightly linked with serum homocysteine levels.…”

Section: Aortic Stiffness and Kynamentioning

confidence: 99%

“…Kynurenic acid (KYNA), a derivative of tryptophan formed along the kynurenine pathway, displays pleiotropic biological effects. KYNA is the only known endogenous antagonist of glutamatergic and α7 nicotinic receptors, as well as a ligand of G-protein coupled receptors 35 (GPR35), and of aryl hydrocarbon receptors (AHR) [14,15]. As a result, KYNA exerts cytoprotective, neuromodulatory and anti-inflammatory effects [14,15].…”

Section: Introductionmentioning

confidence: 99%

“…KYNA is the only known endogenous antagonist of glutamatergic and α7 nicotinic receptors, as well as a ligand of G-protein coupled receptors 35 (GPR35), and of aryl hydrocarbon receptors (AHR) [14,15]. As a result, KYNA exerts cytoprotective, neuromodulatory and anti-inflammatory effects [14,15]. Kynurenine, the first stable product of tryptophan metabolism, can be transaminated either to KYNA, or, along another arm of the path, to the cytotoxic metabolites, such as 3-hydroxykynurenine, 3-hydroxyanthranilic acid or quinolinic acid [15].…”

Section: Introductionmentioning

confidence: 99%

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Aortic stiffness—Is kynurenic acid a novel marker? Cross-sectional study in patients with persistent atrial fibrillation

Zapolski

Kamińska²,

Kocki

et al. 2020

PLoS ONE

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Objective Although a number of modifiable and non-modifiable causes were implicated in arterial stiffness, its pathogenesis remains elusive, and very little is known about aortic elasticity in supraventricular arrhythmias. The potential role of disturbed kynurenine metabolism in the pathogenesis of cardiovascular disease has been recently suggested. Thus, we studied the correlations of aortic stiffness and echocardiographic parameters with biochemical markers and serum level of kynurenic acid (KYNA), an endothelial derivative of tryptophan, formed along the kynurenine pathway, among patients with atrial fibrillation (AF). Methods Study cohort comprised 100 patients with persistent AF (43 females/57 males). Arterial stiffness index (ASI), structural and functional indices of left atrium (LA) and left ventricle (LV) were evaluated electrocardiographically. Biochemical analyses included the measurements of serum KYNA (HPLC) and of the selected markers of lipids and glucose metabolism, thyroid status, kidney function, inflammation and coagulation. Results KYNA (β = 0.389, P = 0.029), homocysteine (β = 0.256, P = 0.40), total cholesterol (β = 0.814; P = 0.044), LDL (β = 0.663; P = 0.44), TSH (β = 0.262, P = 0.02), fT 3 (β =-0.333, P = 0.009), fT 4 (β =-0.275, P = 0.043) and creatinine (β = 0.374, P = 0.043) were independently correlated with ASI. ASI was also independently associated with LV end-systolic diameter (LVEDd; β = 1.751, P = 0.045), midwall fractional shortening (mFS; β =-1.266, P = 0.007), ratio mFS/end-systolic stress (mFS/ESS; β =-0.235, P = 0.026), LV shortening fraction (FS; β =-0.254, P = 0.017), and LA volume index (LAVI; β = 0.944, P = 0.022).

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Correlations of Kynurenic Acid, 3-Hydroxykynurenine, sIL-2R, IFN-α, and IL-4 with Clinical Symptoms During Acute Relapse of Schizophrenia

et al. 2017

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Several lines of evidence suggest that up-regulation of immune response and alterations of kynurenine pathway function are involved in pathogenesis of schizophrenia. Correlations among clinical status (using PANNS, SANS and SAPS scales) and blood levels of kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK) and levels of selected immunoactive molecules, soluble interleukin-2 receptor (sIL-2R), interferon-α (IFN-α) and IL-4 were analyzed in 51 chronic schizophrenia patients during acute relapse, after four weeks of therapy and at remission. KYNA levels were significantly lower in comparison with controls (N=45) throughout the study, whereas 3-HK did not differ from controls at admission and during therapy, but increased at remission. The KYNA/3-HK ratio and IL-4 levels, but not sIL-2R and IFN-α levels, were consistently decreased in schizophrenia patients at all analyzed time points. KYNA level and KYNA/3-HK ratio measured at admission correlated negatively with the duration of illness, whereas 3-HK level correlated negatively with the improvement of SANS score at discharge. sIL-2R level before treatment was positively linked with number of relapses. In the subgroup of patients with poor response to pharmacotherapy, treated with clozapine later on, initial KYNA level and the ratio KYNA/3-HK correlated negatively with number of relapses. Positive association of sIL-2R level with number of relapses was also evident in this subgroup. Furthermore, among these patients, starting IFN-α level was negatively linked with the improvement of total PANSS score at discharge. Presented here data support the concept of disturbed kynurenine pathway function in schizophrenia and suggest that assessment of KYNA and 3-HK levels during acute relapse might be useful in prediction of response to antipsychotic therapy. Deficit of peripheral KYNA and higher 3-HK levels could be associated with more severe symptoms of schizophrenia. Further studies with larger samples size are needed to validate our results.

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Endogenous Kynurenic Acid and Neurotoxicity

Cited by 11 publications

References 204 publications

Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease

Increased expression of kynurenine aminotransferases mRNA in lymphocytes of patients with inflammatory bowel disease

Aortic stiffness—Is kynurenic acid a novel marker? Cross-sectional study in patients with persistent atrial fibrillation

Correlations of Kynurenic Acid, 3-Hydroxykynurenine, sIL-2R, IFN-α, and IL-4 with Clinical Symptoms During Acute Relapse of Schizophrenia

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